A central limiting factor of existing therapeutic strategies in treating neoplasms is tumor heterogeneity and the invasive nature of the tumor. Therefore, effective therapies need to specifically target a diverse and dynamic cell population, as well as attack tumor cells that have migrated beyond the margins of the tumor bulk.
For several decades, immunotherapy has been investigated as a cancer therapy. Successfully harnessing the immune response could result in a specific and adaptive anti-cancer activity at a cellular level. Immunotherapy allows for the targeting of multiple cell types in different compartments. Further, fully engaging the immune system, such as by vaccination, may provide long-term anti-cancer surveillance and protection. Accordingly, if the immune system is fully activated against a cancer the way that it becomes activated against an infection, the body can provide itself with a durable and targeted way to defend against the cancer.
Despite intensive research, however, current immunotherapy approaches have yielded disappointing results. Recent work suggests that the body can generate an antitumor immune response, yet only marginal improvements in survival have been observed. One reason for the disappointing results is the tumor immune microenvironment. Tumor cells have devised a complex set of mechanisms to evade the immune response. Cancers can mute an immune response through several mechanisms, which include, but are not limited to: downregulating the expression of the major histocompatibility complex (MHC), increasing activation of regulatory T cells (Treg), and expressing an immunosuppressive cytokine profile. For example, tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Current methods of active immunotherapy directed to glioblastoma multiforme, as an example, are shown in FIG. 1. Tumor cells, however, can also express immune checkpoint molecules or inhibitors, such as Programmed Death 1 (PD-1), CTLA-4, B7H1, B7H4, OX-40, CD137, CD40, and LAG3, which directly inhibit immune cells and suppress the host's immune response.
Radiation therapy has been long regarded as a directly cytotoxic cancer treatment and is known to be an effective means of reducing tumor bulk. More recent evidence, however, also shows that radiation is able to counteract the immunosuppressive tumor microenvironment to generate an immune response through mechanisms, such as increased MHC class I expression, presentation of normally suppressed carcinoma-associated antigens, increased expression of pro-inflammatory cytokines, and downregulation of the Fas ligand.
Accordingly, radiation is effective in priming the immune system with cancer antigens. Current radiation strategies, however, have limitations. For example, current radiation paradigms radiate a significant margin to include infiltrating cells. This paradigm requires radiating patients for weeks and, as a result, patients have experienced radiation-associated toxicities, including a drop in the white blood cell (WBC) count, which is counterproductive for immunotherapy. In contrast, focused radiation, such as Stereotactic radiosurgery (SRS), allows for a therapeutic dose of radiation while minimizing radiation-associated toxicities. Further, a high dose of radiation can be delivered over one day with SRS.
There exists, therefore, a need for novel cancer immunotherapies which require a combination therapy approach that concurrently activates the immune system using radiation therapy, and bypasses tumor mediated immune suppression.